JP3404749B2 - N- [4- (heteroarylmethyl) phenyl] -heteroarylamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N- [4- (heteroarylmethyl) phenyl] -heteroarylamines, their N-oxides and addition salts; and to processes for their preparation and their inclusion. Which composition. The compounds of the present invention are potent inhibitors of retinoic acid metabolism and therefore
Their use as medicaments is also described.

European Patent Application Publication No. 0,260,744, March 1988 2
Published 3rd, as an inhibitor of androgen production from C ₂₁ -steroids, as an inhibitor of thromboxane A ₂ biosynthesis, and also has the ability to enhance uric acid excretion (1H
-Imidazol-1-ylmethyl) -substituted benzimidazoles are disclosed. European Patent Publication No. 0,371,559, published June 6, 1990, discloses the benzimidazole and its analog benzotriazole as an effective inhibitor of plasma clearance of endogenously or exogenously administered retinoic acid. There is.

Retinoic acid (RA) is a key molecule in the regulation of epithelial tissue proliferation and differentiation. However, RA is metabolized very rapidly by a series of enzymatic reactions, leading to inactivation. Inhibiting RA metabolism enhances RA levels in plasma and tissues. Therefore, compounds with such inhibitory action, also called retinoic acid pseudoactivity, have therapeutic and / or prophylactic potential in the fields of dermatology and oncology.

The novel compounds of the present invention have retinoic acid mimetic activity and, in addition, show little or no endocrine side effects.

The present invention has the formula In the formula, R ¹ represents hydrogen, hydroxy, C ₁ -C ₆ alkyl or aryl; R ² is hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; C _2-
C ₈ alkenyl; aryl; pyrrolidinyl optionally substituted with C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyloxycarbonyl; or C ₃ -C ₇ cycloalkyl,
Hydroxy, C ₁ -C ₄ alkyloxy, cyano, amino,
Mono- and di (C ₁ -C ₄ alkyl) amino, mono- and di (aryl) -amino, aryl C ₁ -C ₄ alkylamino, (C ₁ -C ₄ alkyl) (aryl C ₁ -C ₄ alkyl)
Amino, pyrrolidinyl, piperidinyl, optionally C _1-
Piperazinyl optionally substituted with C ₄ alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C ₁
-C ₄ alkyloxycarbonyl, aminocarbonyl, mono- and di (C ₁ -C ₄ alkyl) aminocarbonyl, C ₁ -substituted by one or two substituents selected from aryl, aryloxy and arylthio. represents C ₁₂ alkyl; R ³ is hydrogen, C ₁ -C ₆ alkyl, aryl; or represents a C ₁ -C ₆ alkyl substituted with aryl; Het is imidazolyl, triazolyl, unsaturated selected from tetrazolyl and pyridinyl Represents a heterocycle; each of the unsaturated heterocycles is optionally amino, mercapto, C _1-
Optionally substituted with C ₆ alkyl, C ₁ -C ₆ alkylthio or aryl; Represents an unsaturated monocyclic or bicyclic heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, purinyl, phthalazinyl, cinnolinyl, quinazolinyl and quinoxalinyl; Or each of the bicyclic heterocycles is optionally hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo.
C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkylthio, formyl, carboxyl, mono- - or di (C ₁
-C ₆ alkyl) amino, one selected from C ₁ -C ₆ alkyloxycarbonyl or aryl, or two or three may be substituted with a substituent; or Is an expression Wherein each X is independently NR ⁸ , O, S, S (= O) or S (=
O) ₂ ; R ⁸ is hydrogen, C ₁ -C ₆ alkyl, aryl or aryl C ₁ -C ₆ alkyl; R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halo, cyano, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁
-C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- - or di (C ₁ -
C ₆ alkyl) represents amino, C ₁ -C ₆ alkyloxycarbonyl or aryl; -R ⁶ -R ⁷ - is the ^{formula: -CR 9 = CR 9 -CR 9} = CR 9 -, (b-1); - ^{N = CR 9 -CR 9 = CR} 9 -, (b-2); -CR 9 = N-CR 9 = CR 9 -, (b-3); -CR 9 = CR 9 -N = CR 9 -, ^{(b-4); -CR 9} = CR 9 -CR 9 = N-, (b-5); -CR 9 = N-N = CR 9 -, (b-6); -CR 9 = N-CR ^{9 = N-, (b-7} ); -CR 9 = CR 9 -N = N-, (b-8); -N = N-CR 9 = CR 9 -, (b-9); -N = ^{CR 9 -N = CR 9 -,} (b-10); -N = CR 9 -CR 9 = N-, (b-11); -CR 9 = N-N = N-, (b-12); ^{= N-, -N = CR 9 -N} (b-13); -N = N-CR 9 = N-, (b-14); -N = N-N = CR 9 -, (b-15) Represents a divalent group of, where each R ⁹ is Hydrogen, hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- Or di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkyloxycarbonyl or aryl; and aryl is phenyl; or hydroxy, halo, cyano, amino, mono- or di (C ₁ -C ₆ alkyl) ) Amino, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, hydroxy
Represents phenyl substituted with 1, 2 or 3 substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl and C ₁ -C ₆ alkylcarbonyl; Alternatively, two adjacent carbon atoms on said phenyl may be substituted by one divalent group having the formula C ₁ -C ₁₂ alkanediyl or halo C ₁ -C ₁₂ alkanediyl , N-oxides, their pharmaceutically acceptable addition salts or stereochemically isomeric forms.

As used in the definitions above and below, halo is a generic term for fluoro, chloro, bromo and iodo; C ₃
-C ₇ cycloalkyl is cyclopropyl, cyclobutyl,
Cyclopentyl, be a generic cyclohexyl and cycloheptyl; C ₂ -C ₈ alkenyl is, for example, ethenyl, 1-propenyl, 2-butenyl, 2-pentenyl,
A straight chain containing one double bond and having 2 to 8 carbon atoms such as 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl and the like; Represents a branched chain hydrocarbon group; C ₁ -C ₄ alkyl is, for example, _{1 to} such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl, etc. Represents straight-chain and branched-chain hydrocarbon radicals having 4 carbon atoms; C ₁ -C ₆ alkyl is C ₁ -C ₄ alkyl and, for example, pentyl, 2-
It is intended to include their higher homologues having 5 to 6 carbon atoms such as methylbutyl, hexyl, 2-methylpentyl and the like; C ₁ -C ₁₂ alkyl is C ₁ -C ₆ alkyl and For example, heptyl, octyl, nonyl,
Decyl, undecyl, dodecyl, 2-methylhexyl,
Meant to include their higher homologues having 7 to 12 carbon atoms such as 3-ethyloctyl and the like; C
₁ -C ₁₂ alkanediyl, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4
Butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,7
-Heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl, 1,1,4,4-tetramethylbutane-1,4 Represents divalent straight chain and branched chain saturated hydrocarbons having 1 to 12 carbon atoms, such as diyl; halo C ₁ -C ₆ alkyl is polyhalo-substituted C _1-
C ₆ alkyl, especially C ₁ -C ₆ alkyl substituted with 1 to 6 halogen atoms, more particularly defined as difluoro- or trifluoromethyl; halo C ₁ -C ₁₂ alkanediyl is polyhalo substituted C ₁ -C ₁₂ alkanediyl, especially C ₁ -substituted with 1 to 12 halogen atoms
Defined as C ₁₂ alkanediyl; triazolyl is 1,2,4-
It is meant to include triazolyl and 1,3,4-triazolyl; tetrazolyl is meant to include 1H-tetrazolyl and 2H-tetrazolyl.

The unsaturated heteroaryl group represented by Het may be attached to the rest of the molecule of formula (I), suitably via any ring carbon or heteroatom. Therefore,
For example, when the heteroaryl group is imidazolyl,
It may also be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl it is 1,2,4-triazolyl-1-yl, 1,2,4-triazolyl- 3-yl, 1,2,4
-Triazolyl-5-yl, 1,3,4-triazolyl-1
It may be -yl and 1,3,4-triazolyl-2-yl.

The pharmaceutically acceptable addition salts described above are meant to comprise the therapeutically active non-toxic base and acid addition salt forms that the compounds of formula (I) are able to form. Acid addition salt forms of the compounds of formula (I) which are present in their free form as a base are obtained by converting the free base form into an inorganic acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, Or a suitable acid such as phosphoric acid; or, for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, It can be obtained by treatment with an organic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like.

Compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic bases, ie metals or amines, addition salt forms by treatment with suitable organic and inorganic bases. . Suitable base salt forms include salts with organic bases such as ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, for example,
It comprises benzathine, N-methyl-D-glucamine, hydrabamin salts and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, the salt form can be converted to the free form by treatment with a suitable base or acid.

The term addition salt as used above also comprises the compounds of formula (I) as well as the solvates which the salts are able to form. Such solvates are, for example, hydrates, alcoholates and the like.

The N-oxide form of the compounds of formula (I) is meant to comprise compounds of formula (I) in which one or several nitrogen atoms have been oxidized to so-called N-oxides.

The term "stereochemically isomeric form" as used above and below refers to all possible isomeric forms in which a compound of formula (I) may exist. Unless otherwise noted or indicated, the chemical designations of compounds refer to the mixtures of all possible stereochemically isomeric forms, and especially racemic mixtures, which mixtures include all diastereomers and enantiomers of the basic molecular structure. contains. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are clearly intended to be encompassed by formula (I).

In particular, the compounds of formula (I) and some of the intermediates mentioned below have at least one stereogenic center in their structure. Stereogenic centers may exist in the R and S configurations and the R and S notations are used corresponding to the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms are not explicitly indicated in the above formula, but are intended to be included within the scope of the present invention. In particular, compounds of formula (I) in which R ³ is hydrogen may exist in their corresponding tautomeric form.

As used below, the term compound of formula (I) is also meant to include N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms.

A particular group of compounds is that R ¹ represents hydrogen, C ₁ -C ₆ alkyl or aryl; R ² is hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; C _2-
C ₈ alkenyl; aryl; or C ₃ -C ₇ cycloalkyl, hydroxy, C ₁ -C ₄ alkyloxy, cyano, amino, mono- and di (C ₁ -C ₄ alkyl) amino, mono-
And di (aryl) amino, aryl C ₁ -C ₄ alkylamino, (C ₁ -C ₄ alkyl) (aryl C ₁ -C ₄ alkyl) amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, perhydro-azepinyl, carboxyl, C ₁ -C ₄ alkyloxycarbonyl, aminocarbonyl, mono- - and di (C ₁ -C ₄ alkyl) aminocarbonyl, aryl, C ₁ substituted with one or two substituents selected from aryloxy and arylthio
Represents -C ₁₂ alkyl; Is 2-pyridinyl, 3-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 1-phthalazinyl, 3-cinnolinyl, 2-quinazolinyl, 4
-Represents an unsaturated monocyclic or bicyclic heterocycle selected from the group consisting of quinazolinyl and 2-quinoxalinyl;
Each of said unsaturated mono- or bicyclic heterocycles is optionally hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl,
One selected from C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- or di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkyloxycarbonyl or aryl,
It may be substituted with 2 or 3 substituents, or However, R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C _1-.
C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- or di (C ₁ -C ₆
It comprises a compound of formula (I) which represents a group of formula (a) or (b) representing alkyl) amino, C ₁ -C ₆ alkyloxycarbonyl or aryl.

A group of compounds of interest is where R ¹ represents hydrogen, hydroxy, C ₁ -C ₆ alkyl; R ² is hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; optionally C _1- Pyrrolidinyl optionally substituted with C ₄ alkyl or C ₁ -C ₄ alkyloxycarbonyl; aryl; or hydroxy, C ₁ -C ₄ alkyloxy, mono- and di (C ₁ -C ₄ alkyl) amino, (C _1- C ₄ alkyl) (arylC ₁ -C ₄ alkyl) amino, C ₁ -C ₄ alkyloxycarbonyl, morpholinyl, piperidinyl, piperazinyl optionally substituted with C ₁ -C ₄ alkyl, and aryloxy Represents C ₁ -C ₁₂ alkyl substituted with one or two substituents selected from: R ³ represents hydrogen and C ₁ -C ₆ alkyl; Het optionally represents C ₁ -C ₆ alkyl Even if it is replaced Good imidazolyl; represents pyridinyl or triazolyl; Is optionally substituted with hydroxy C ₁ -C ₆ alkyl, formyl or C ₁ -C ₆ alkyloxycarbonyl; 2-pyridinyl; 2-quinoxalinyl; 1-isoquinolinyl; 2-quinolinyl; optionally C ₁ -C 3-pyridazinyl optionally substituted with ₆ alkyl; purinyl; 2-pyrazinyl; 1-phthalazinyl; 4-quinazolinyl optionally substituted with aryl; 2-pyrimidinyl; optionally C ₁ -C ₆ alkylthio 4 which may be substituted
-Represents pyrimidinyl; or Represents a group of formula (a) or (b), wherein X represents NH, O or S; R ⁴ and R ⁵ are each independently hydrogen, hydroxy, nitro,
Cyano, amino, C ₁ -C ₆ alkyl or aryl, and —R ⁶ —R ⁷ — is represented by formula (b-1), (b-2) or (b-
10) divalent radicals in which each R ⁹ is independently hydrogen, C ₁
-C ₆ alkyl, hydroxy, halo, amino, halo C ₁ -C ₆
It comprises a compound of formula (I) representing alkyl or C ₁ -C ₆ alkyloxy.

Het is optionally substituted imidazolyl or triazolyl, especially _1- imidazolyl optionally substituted with C ₁ -C ₆ alkyl or aryl; optionally substituted with C ₁ -C ₆ alkyl Good 2-imidazolyl; 5-imidazolyl optionally substituted with C ₁ -C ₆ alkyl; a formula which is 1,3,4-triazol-1-yl and 1,2,4-triazol-1-yl Those compounds of (I) are of particular interest.

There group of formula (b), in particular represent them, wherein, X represents O or S; and -R ⁶ -R ⁷ - represents a bivalent radical of formula (b-I), formula (I The compounds shown in () are also of special interest.

Other compounds of particular interest are those where R ² is C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; aryl; or mono-
Or a compound of formula (I) representing C ₁ -C ₁₂ alkyl substituted with di (C ₁ -C ₄ alkyl) amino, C ₁ -C ₄ alkyloxycarbonyl or aryloxy.

Certain compounds include 1-imidazolyl, wherein Het is optionally substituted with C ₁ -C ₆ alkyl or aryl; 2-imidazolyl optionally substituted with C ₁ -C ₆ alkyl; optionally C it is 1,3,4-triazol-1-yl and 1,2,4-triazol-1-yl;; ₁ -C ₆ alkyl optionally substituted 5-imidazolyl R ² is C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; aryl; or mono - represents or di (C ₁ -C ₄ alkyl) C ₁ -C ₁₂ substituted with amino; and Is the expression Where X is O or S are those compounds of particular interest.

Preferred compounds are those in which R ¹ is hydrogen and R ² is C ₃ -C ₇
Cycloalkyl or optionally di (C ₁ -C ₆ alkyl)
Those compounds of formula (I) which are C ₁ -C ₆ alkyl optionally substituted with amino.

The following compound, N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -2-benzothiazolamine; N- [4- [2-ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzoxa N- [4- [2-Ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzothiazolamine; N- [4- [2- ( Dimethylamino) -1- (1H-imidazol-1-yl) propyl] phenyl] -2-benzothiazolamine; N- [4- [2- (dimethylamino) -1- (1H-1,2,
4-triazol-1-yl) propyl] phenyl]-
2-benzothiazolamine; N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -2-benzoxazolamine; N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -6-methoxy-2-benzothiazolamine; N- [4- [2- (dimethylamino) -1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] 2-benzothiazolamine; N- [4- [2- (dimethylamino) -2-methyl-1
-(1H-1,2,4-triazol-1-yl) propyl]
Phenyl] -2-benzothiazolamine; N- [4- [cyclohexyl (1H-imidazol-1-
N- [4- [cyclohexyl (1H-1,2,4-triazol-1-yl) methyl] phenyl] -2-benzothiazolamine, their N- Most preferred are the oxides, stereochemically isomeric forms or pharmaceutically acceptable addition salts.

As used below, R ^{1 to} R ³ , Het, aryl and Are defined under formula (I) unless otherwise stated.

In general, compounds of formula (I) may be prepared by converting an intermediate of formula (II) where W ¹ is a suitable leaving group, such as, for example, a halogen, hydroxy or alkylsulfonyloxy group, to a compound of formula (II
It can be produced by reacting with the intermediate of I) or a functional derivative thereof. For example, the functional derivative of imidazole may be 1,1'-carbonyldiimidazole.

The reaction may be carried out in a reaction inert solvent such as acetonitrile or tetrahydrofuran in the presence of a suitable base such as potassium carbonate. When W ¹ is a hydroxy group, it may be convenient to carry out the above reaction in the presence of triphenylphosphine and diethyl azodicarboxylate or a functional derivative of either of the reagents.

In this and the following production method, the reaction product is isolated from the reaction medium and, if necessary, further, for example:
It may be purified according to methods generally known in the art such as extraction methods, crystallization methods, distillation methods, milling methods and chromatographic methods.

Alternatively, the compound of formula (I) may be prepared by converting the intermediate of formula (IV) to an intermediate of formula (I) wherein W ² is a suitable leaving group, eg a phenoxy group, eg N 2 It may also be prepared by N-alkylation in a reaction-inert solvent such as, N-dimethylformamide.

Is a group of formula (a) [wherein X represents S], the compound being represented by formula (Ia-1), is an intermediate of formula (VI) The compounds can be prepared by reacting with an intermediate of formula (VII) in which W ³ is a suitable leaving group, in a reaction inert solvent such as, for example, tetrahydrofuran.

Suitably the intermediates of formula (VII) may be replaced by their functional derivatives, eg their ketalized derivatives. If the carbonyl group in the intermediate of formula (VII) is ketalized, the reaction is suitably carried out in the presence of an acid, eg hydrochloric acid.

R ³ is hydrogen, and Is a group of formula (b) [wherein X represents S], the compound of formula (Ib-1) is an intermediate of formula (VIII) And the intermediate of formula (IX-1) in a reaction-inert solvent such as tetrahydrofuran or 1-methyl-2-pyrrolidinone,
It can be produced by reacting.

In the above reaction, the intermediate (IX-1) has the formula (IX-2)
A compound of formula (Ia-1), wherein R ³ is hydrogen and R ⁴ is amino.
The compound may be represented by formula (Ia-2).

As an alternative to intermediate (VIII), the reaction may also be carried out using the intermediate of formula (X). In that case,
The reaction is carried out in a reaction inert solvent such as dimethylsulfoxide and in the presence of a suitable base such as sodium hydroxide.

Compounds of formula (I) in which R ¹ is hydroxy include R ¹ and
Intermediates corresponding to compounds of formula (I) in which R ² together with the carbon atom to which they are attached form a carbonyl group, are described with Het-H (III) or functional derivatives thereof, for example: It can be prepared by reacting in the presence of a suitable reagent such as n-butyllithium in a reaction-inert solvent such as tetrahydrofuran and optionally in the presence of chlorotriethylsilane.

Compounds of formula (I) in which R ² is C ₁ -C ₄ alkyloxy C ₁ -C ₁₂ alkyl include compounds wherein R ² is L-C ₁ -C ₁₂ alkyl [wherein L is, for example, an alkylsulfonyloxy group. is a suitable leaving a radical intermediates corresponding to compounds of formula (I), C ₁ -C ₄ alkyl O such as ^- M ⁺ [wherein, M ⁺ is, for example, such as Na ⁺ It is a suitable metal ion] in a suitable solvent such as methanol.

Compounds of formula (I) in which R ² is optionally substituted C ₁ -C ₁₂ alkyl include compounds of the formula (I) in which R ² is bonded to the carbon atom bearing the R ² substituent by a double bond. Intermediates corresponding to compounds of I) can be prepared by reduction using a suitable reducing agent such as sodium borohydride in a suitable solvent such as methanol.

The compounds of formula (I) can also be converted into each other according to procedures known in the art for functional group transformations.

For example, compounds of formula (I) R ³ is hydrogen may be converted into compounds of formula (I) R ³ is other than hydrogen.

In addition, the compound of formula (I) containing a C ₁ -C ₆ alkyloxycarbonyl substituent has the substituent reduced to hydroxymethyl; It may be converted to an optionally converted compound of formula (I).

Compounds of formula (I-a-2) R 5 is cyano further reacted with HN = CH-NH ₂ or a functional derivative thereof, thus -R ⁶ -R ⁷ - is -N = CH- N = C (NH ₂₎ -
Corresponding compounds of formula (Ib-1) can be produced.

Compounds of formula (I) where R ¹ is hydroxy can be converted to compounds of formula (I) where R ¹ is hydrogen using a suitable reagent such as tin (II) chloride.

The compound of formula (I) may also be converted to the corresponding N-oxide form according to procedures known in the art for converting a trivalent nitrogen to its N-oxide form. The N-oxidation reaction is generally carried out by converting the starting material of formula (I) to 3-
It may be carried out by reduction with phenyl-2- (phenylsulfonyl) oxaziridine or a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include, for example, benzene. Carboperoxo acids or halo-substituted benzenecarboperoxoic acids, such as 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, such as peroxoacetic acid, alkylhydroperoxides, such as peroxyacids such as t-butylhydroperoxide. May be Suitable solvents include, for example:
Water, lower alkanols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Some of the compounds of formula (I) and some of the intermediates in the present invention may contain asymmetric carbon atoms. Pure stereochemically isomeric forms of the compounds and intermediates can be obtained by applying procedures known in the art. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic methods such as countercurrent partitioning, liquid chromatography and the like. Enantiomers are converted from a racemic mixture by first converting the racemic mixture into a diastereoisomeric salt or mixture of compounds with a suitable resolving agent such as chiral acid; then a diastereomeric salt or The compound is physically separated, for example by selective crystallization or chromatographic methods, such as liquid chromatography, and finally, the separated diastereoisomeric salt or compound is separated into the corresponding enantiomers It can be obtained by converting to. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reaction occurs stereospecifically.

An alternative method for separating the enantiomeric forms of the compounds of formula (I) and intermediates includes liquid chromatography methods, especially those using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds and are either commercially available or may be prepared according to procedures known in the art.

In particular, R ¹ and R ³ are hydrogen and W ¹ is hydroxy, and Is a group of formula (b), an intermediate of formula (II), said intermediate being represented by formula (II-b-1). ) Or (XI-2) intermediate, followed by reduction of the intermediate thus formed.

The first reaction is described hereinabove in order to prepare a compound of formula (Ib-1) starting from an intermediate of formula (IX) and an intermediate of formula (VIII) or (X). Includes the same procedure used. The reduction may be carried out in the presence of a suitable reducing agent, for example in a suitable reaction inert solvent such as sodium borohydride in methanol or tetrahydrofuran and lithium aluminum hydride in water.

In some examples, the hydroxy group in the intermediate of formula (II-b-1) is replaced by another leaving group such as, for example, a halogen or sulfonyl derivative, such as a p-toluenesulfonyloxy group or an alkylsulfonyloxy group. By the formula (II-b-2) or (II-b-
It may be convenient to produce the intermediate of 3). The reaction can be carried out in a reaction inert solvent such as chloroform and in the presence of a suitable reagent such as thionyl chloride or methylsulfonyl chloride.

Intermediates of formula (IV) are intermediates of formula (XII) in which P is, for example, C ₁ -C ₄ alkylcarbonyl, benzoyl or C ₁ -C ₄ alkyloxycarbonyl, intermediates of formula (III) May be prepared by reacting the amide derivative thus formed with an acid such as hydrochloric acid. The production of the intermediate amide derivative is
Starting from the intermediates of formula (II) and (III), the formula (I)
Which may be carried out using the same procedure used for the preparation of the compounds of

The intermediate of formula (VI) further comprises an intermediate of formula (IV) of two suitable reagents, for example NH ₄ SCN in combination with benzoyl chloride or a functional derivative of any one of said reagents. It can be produced by reacting the combination with a combination in a reaction-inert solvent such as 2-propanone. The intermediate thus produced may be deprotected, for example using a suitable base such as sodium hydroxide.

An intermediate of formula (IV) wherein R ₃ is hydrogen, said intermediate being of formula (IV
-Represented by a) is also in the presence of a suitable reagent such as CSCl ₂ or a functional derivative thereof, in a reaction inert solvent and in the presence of a suitable base such as sodium hydroxide. The reaction may be carried out thus forming the intermediate of formula (VIII).

In addition, the intermediate of formula (IV-a) may be further used during the production of the intermediate of formula (X). The production method comprises the step of converting the intermediate of the formula (IV-a) into a reaction-inert solvent with CS ₂ and CH ₃ -I or a functional derivative of any one of the reagents and, for example, sodium hydroxide. Reaction in the presence of such a base.

The compounds of formula (I) inhibit plasma depletion of retinoids such as all-trans-retinoic acid, 13-cis-retinoic acid and their derivatives, further maintain plasma and tissue concentrations of retinoic acid and Improves regulation of cell type differentiation and proliferation. This action of the compound is also called rethioic acid pseudoactivity, since the administration of the compound of formula (I) produces the same effect as if the retinoid were administered. As such, the compound
Whether they are epithelial or mesodermal;
Whether they are of ectodermal, endodermal or mesodermal origin, they can be used to regulate the growth and differentiation rates of normal cells, preneoplastic cells and tumor cells.

The property of slowing the metabolism of retinoic acid can be demonstrated in various in vitro and in vivo experiments. A specific ex vivo procedure is described in Example C.1 and tests the inhibitory activity of the compounds of formula (I) on the metabolism of retinoic acid in human breast cancer cells. The compound of the present invention was also effective in suppressing the induced vaginal keratinization effect in ovariectomized rats, as described in Example C.2.

Moreover, the compounds of formula (I) show little or no endocrine side effects and they have good oral availability.

In view of the above pharmaceutical properties, in particular their retinoic acid mimetic activity, the compounds are useful in the treatment of disorders characterized by abnormal proliferation and / or abnormal differentiation of cells, especially cells whose proliferation and differentiation are sensitive to the action of retinoids. Effective for treatment and / or prevention. Such disorders are in the field of oncology,
For example, head-and-neck cancer, lung cancer, breast cancer, cervical cancer, gastrointestinal tract cancer, skin cancer, bladder cancer and prostate cancer and similar disorders; and the field of dermatology, eg rosacea, acne, psoriasis, severe. Psoriasis, lamellar ichthyosis, plantar warts, tongue, black surface hyperplasia, lichen planus, molluscum, melanosis, corneal epithelium, geographical tongue, Fox-Fordyce disease, skin metastases Melanoma and keloids, keratoproliferative hyperkeratosis, Darier disease,
It is located in keratinizing disorders such as Rubella pyralis, congenital ichthyosis erythema, palmar and plantar hyperkeratosis, melasma, hyperpigmentation and similar disorders.

In addition, the compound of formula (I) is administered exogenously and produced endogenously, 1α, 25-dihydroxy-vitamin D.
It is effective in suppressing the metabolism of ₃ (calcitriol). The inhibitory activity of the compounds of formula (I) on the metabolic degradation of calcitriol may be demonstrated by measuring the impact of the compounds on the degradation of calcitriol in human foreskin keratinocytes, porcine kidney cells and human hepatoma cells. . In light of their inhibitory effect on calcitriol metabolism, compounds of formula (I) can be used for the treatment of vitamin D deficiency conditions. The "classical" application of vitamin D compounds is in the field of metabolic bone disorders. Calcitriol has also been described to affect the effects and / or production of interleukins. In addition, calcitriol is useful in the treatment of diseases characterized by abnormal cell proliferation and / or differentiation, especially keratinization disorders such as those described above (Bouillon et al., En.
docrine Reviews, 1995, 16, 200-257).

In light of the above use of the compounds of formula (I), the present invention, whether they are epithelial or mesodermal; they are of ectodermal, endodermal or mesodermal origin. Whether or not, it provides a method of treating warm-blooded animals afflicted with a disease characterized by abnormal proliferation and abnormal differentiation of normal cells, preneoplastic cells and tumor cells. The method provides a compound of formula (I) effective for treating the above disorders, especially keratinizing disorders such as psoriasis, optionally in the presence of an effective amount of retinoic acid derivatives or stereochemically isomeric forms thereof. Systemically or locally administering a retinoic acid-mimicking amount. The invention further comprises
A method of treating a patient suffering from a pathological condition that may be advantageously affected by the administration of calcitriol or a prodrug thereof, in particular a keratinization disorder such as psoriasis, said method comprising the steps of (a) calcitriol or It consists of administering an effective amount of these prodrugs and (b) an effective amount of a compound of formula (I).

Therefore, the present invention is also for use as a drug,
In particular it relates to a compound of formula (I) as defined above for use in the manufacture of a medicament for the treatment of keratinizing disorders such as psoriasis. The present invention further provides a compound of formula (I) as defined above in combination with retinoic acid, their derivatives or stereochemically isomeric forms, or in combination with calcitriol or a prodrug thereof, for use as a drug. Regarding

To facilitate administration, the subject compounds may be formulated into various pharmaceutical forms. As suitable compositions, all compositions commonly used in the case of drugs to be administered systemically or locally may be cited. To prepare the pharmaceutical compositions of the present invention, the active ingredient, a retinoic acid pseudo-effective amount of a particular compound, optionally in addition salt form, is combined in intimate admixture with a pharmaceutically acceptable carrier. , It may take a wide variety of forms depending on the form of preparation required for administration. These pharmaceutical compositions are preferably in unit dosage form, suitable for administration by oral, rectal, transdermal, or parenteral injection. For example, when preparing a composition for oral dosage form, for example, oral liquid preparations such as suspensions, syrups, elixirs and solutions, usual liquids such as water, glycol, oil, alcohol, etc. Any pharmaceutical medium may be used; or in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrating agents and the like may be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are expressly employed. In the case of parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, that aid in solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution and a mixture of saline and glucose solution. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with suitable additives of either nature, in minor proportions, The additive does not cause any significant detrimental effects on the skin. The additive may facilitate administration to the skin and / or may serve to produce the desired composition. These compositions may be administered in various ways, for example as a transdermal patch, spot-on or as an ointment. Addition salts of the compounds of formula (I) have, due to their increased water solubility due to the corresponding base form,
It is clearly more suitable for the production of aqueous compositions.

Suitable compositions for topical administration include all compositions commonly used for topical administration of drugs, such as creams, jellies, dressings, shampoos, colorants, pastes, ointments. Agent, ointment (salv
e), powders and the like may be cited. The composition may be applied, for example, with propellants such as nitrogen, carbon dioxide, freons, or with propellant-free aerosols such as pump sprays, drops, lotions or by swabs. It may also be a semi-solid, such as a concentrated composition that is possible. In certain compositions, ointments,
Semi-solid compositions such as creams, jellies, ointments and the like are conveniently used.

It is especially advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage forms used in the specification and claims are:
A unit dosage refers to a physically discrete unit, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, injectable solutions or suspensions, teaspoonfuls,
Such as a tablespoon, and their segregat
ed multiples).

Other such compositions are cosmetic formulations such as toilet water, packs, lotions, skin milks or milky lotions. The formulation contains, in addition to the active ingredient, ingredients normally used in such formulations. Examples of such ingredients are oils, fats, waxes, surfactants, humectants, sizing agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, fragrances, dyes, lower alkanols and the like. If desired, further ingredients may be incorporated into the composition, for example anti-inflammatory, anti-bacterial, anti-fungal, antiseptic, vitamin, sunscreen, antibiotic or other anti-acne agents. Good.

The invention also provides a particular pharmaceutical or cosmetic composition comprising an inert carrier, an effective amount of a compound of formula (I) and an effective amount of retinoic acid, a derivative thereof or a stereochemically isomeric form thereof. I will provide a. The rethioic acid-containing composition is particularly useful for the treatment of acne or for delaying the symptoms of skin aging and generally improves the quality of the skin, especially human facial skin.

Furthermore, the present invention also relates to particular pharmaceutical or cosmetic compositions comprising an inert carrier, an effective amount of a compound of formula (I) and an effective amount of calcitriol or a prodrug thereof. The latter composition is particularly useful for treating keratinization disorders.

The invention also relates to a product containing retinoic acid and its derivatives and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in dermatological or oncological disorders. The invention also relates to a product containing calcitriol or a prodrug thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in disorders which are beneficially affected by calcitriol. Such products may, for example, comprise a kit comprising a container having a suitable composition containing a compound of formula (I) and a container having a composition containing calcitriol or a retinoid. Such a product may have the advantage that the physician may choose the appropriate amount of each ingredient and the sequence and timing of their administration based on the diagnosis of the patient to be treated.

One of ordinary skill in the treatment of the disorders described above can determine the therapeutically effective amount per day from the test results presented in the experimental part. The effective daily dose is about 0.01 mg / kg to about 40 mg /
kg body weight, more preferably about 0.1 mg / kg to about 10 mg / kg body weight. It may be appropriate to administer a therapeutically effective dose once daily or two, three, four or more sub-doses at appropriate intervals throughout the day. The sub-dose may, for example, be formulated as a unit dosage form containing 0.1 mg to 500 mg of active ingredient per unit dosage form.

The exact dose and number of doses will be well known to those skilled in the art, as will the specific compound of formula (I) used,
It will depend on the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medications the patient may be taking. Furthermore, it will be appreciated that the daily effective amount may be lower or higher depending on the response of the patient to be treated and / or depending on the evaluation of the physician prescribing the compounds of the present invention. Therefore, the ranges of effective daily doses given above are only guidelines.

The following examples are intended to illustrate the invention and not limit the scope of the invention.

Experimental Part Of some compounds of formula (I), the absolute stereochemical configuration of the stereogenic carbon atom therein has not been experimentally determined. In those cases, moreover, regardless of the actual stereochemical configuration, the first isolated stereochemically isomeric form was designated "A" and the second was designated "B". The "A" and "B" forms of those compounds of formula (I) in which there are two stereogenic carbon atoms are
Separated into their pure stereochemically isomeric forms, and further, regardless of the actual stereochemical configuration, "A1" and "A
2 "and" B1 "and" B2 ".

As used below, “THF” is defined as tetrahydrofuran, “EtOAc” is defined as ethyl acetate and “D
"IPE" is defined as diisopropyl ether, and "R
"T" is defined as room temperature.

A) Preparation of Intermediate Compounds Example A-1 a) Benzoyl chloride (0.067 mol) was added to a solution of aminothiocyanate (5.09 g) in 2-propanone (150 ml) and the mixture was stirred for 20 minutes. Refluxed. 4- [1- (1H-imidazole-1) in 2-propanone (150 ml)
-Yl) -2-methylpropyl] benzenamine (0.05
57 mol) solution was added, the mixture was stirred and refluxed at 80 ° C. overnight. The mixture was cooled, filtered through Celite,
The filtrate was evaporated. The residue was dissolved in CH ₂ Cl _2. The organic layer was dried, filtered and the solvent was evaporated. The residue was subjected to column chromatography on silica gel (eluent: CH ₂ Cl ₂ /
CH ₃ OH / NH ₄ OH 98/2 / 0.1). The pure fractions were collected and the solvent was evaporated, leaving 15.2 g (72
%) Of (±) -N-benzoyl-N '-[4- [1-
(1H-imidazol-1-yl) -2-methylpropyl] phenyl] thiourea (intermediate 1) was obtained.

b) Intermediate (1) (0.0329 mol) in NaOH (300 ml; 3N)
The mixture was stirred and refluxed for 2 hours. Cool the mixture,
It was poured into ice, neutralized with concentrated HCl, and extracted with CH ₂ Cl ₂ .
The organic layer was dried, filtered and the solvent was evaporated to 7.91 g (8
8%) of N '-[4- [1- (1H-imidazol-1-
Il) -2-methylpropyl] phenyl] thiourea (Intermediate 2) was obtained.

Example A-2 a) sec Butyllithium (298 ml; 1.3M) was added to THF (400 m).
l) in N- (4-bromophenyl) acetamide (0.1
892 mol) was added dropwise at −60 ° C. under N ₂ stream, and the mixture was stirred at −70 ° C. for 2 hours. 1-Cyano-1-methyl-N, N-di-methylethanamine (0.0
Solution (75 mol) was added dropwise, the mixture was allowed to come to room temperature and then stirred at room temperature for 12 hours. Pour the mixture into ice and wash with EtOA.
Extracted with c. The solvent was evaporated, the residue was HCl (3N) and
Dissolved in EtOAc, extracted with EtOAc, basified with K ₂ CO ₃ (10%) and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was recrystallized from (C ₂ H ₅ ) ₂ O and DIPE. The precipitate is filtered, dried and 6.8g
(36%) of N- [4- [2- (dimethylamino) -2-
Methyl-1-oxopropyl] phenyl] acetamide (Intermediate 3) was obtained.

b) A mixture of intermediate (3) (0.026 mol) in HCl (180 ml; 6N) was stirred and heated at 100 ° C for 2 hours. The mixture was poured into ice, washed with EtOAc, basified with NH ₄ OH, Et.
Extracted with OAc. The organic layer was separated, dried, filtered, the solvent was evaporated and 5.1 g (94%) of 1- (4-amino-phenyl) -2- (dimethylamino) -2-methyl-1-
Propanone (intermediate 4) was obtained.

c) Carbonothioic acid dichloride (2.45 ml) was added with NaOH (1
0.7 ml; 3N) and CHCl ₃ Intermediate (200ml) (4) (0 .
0247 mol) solution at 0 ° C. and the mixture at 4 ° C. at 4 ° C.
Stir for hours. Pour the mixture into K ₂ CO ₃ (10%) and add C
Extracted with H ₂ Cl ₂ . The organic layer is separated, dried, filtered,
The solvent was evaporated to give 6.1 g (99%) of 2- (dimethylamino) -2-methyl-1- (4-isothiocyanatophenyl) -1-propanone (Intermediate 5).

d) A mixture of intermediate (5) (0.0247 mol) and 2-aminobenzenethiol (0.0298 mol) in THF (60 ml) was stirred, refluxed for 2 hours and then further stirred at room temperature for 72 hours. The mixture was poured into water and extracted with EtOAc.
The organic layer was separated, dried, filtered and the solvent was evaporated.
The residue was crystallized from (C ₂ H _{5) 2} O and DIPE. The precipitate was filtered, dried and 5.57 g (67%) of 1- [4- (2-
Benzothiazolylamino) phenyl] -2- (dimethylamino) -2-methyl-1-propanone (intermediate 6) was obtained.

e) NaBH ₄ (3.72 g) was added portionwise at 10 ° C. to a solution of intermediate (6) in methanol (60 ml) and the mixture was stirred at room temperature for 24 hours. Pour the mixture into water and ice and add CH
Extracted with ₂ Cl ₂ . The organic layer is separated, dried, filtered,
The solvent was evaporated to give 5.2 g (93%) of 1- [4- (2-benzothiazolylamino) phenyl] -2- (dimethylamino) -2-methyl-1-propanool (Intermediate 7).
Got

Example A-3 a) A solution of lithium tetrahydroaluminate (0.1107 mol) in THF (100 ml) was suspended in 4- (2-benzothiazolylamino) -ethyl benzoate (0.1107 mol) in water. Was added dropwise at 0 ° C. under a N ₂ stream. The mixture was warmed to room temperature and stirred for 30 minutes. Water (8 ml) was added dropwise, then CH ₂ Cl
₂ (50 ml) was added to hydrolyze the mixture and a small amount of CH ₃
OH was added. The precipitate was filtered and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE. The precipitate was filtered and dried to give 8g (86%) of 4- (2-benzothiazolylamino) benzenemethanol (Intermediate 8).

b) Thionyl chloride (10 ml) was added dropwise to a solution of intermediate (8) (0.039 mol) in CH ₂ Cl ₂ (100 ml) at 0 ° C and the mixture was stirred at 0 ° C for 2 hours. Evaporate the solvent to 10.7
Obtained g of N- [4- (chloromethyl) phenyl] -2-benzothiazolamine (Intermediate 9).

Example _{A-4 a) CH 2 Cl} 2 (200ml) and N, N- dimethylformamide (10ml) of intermediate (8) (0.0312 mol) and stirred for 12 hours at room temperature a mixture of manganese dioxide (0.115 mol) did. Manganese dioxide (0.115 mol) was added again and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through celite, washed with CH ₂ Cl _2, the solvent was evaporated. Water (100m
l) was added, evaporated, filtered, crystallized, filtered,
Drying gave 7 g (89%) of 4- (2-benzothiazolylamino) benzaldehyde (Intermediate 10).

b) A solution of 1-bromo-3-fluorobenzene (0.213 mol) in THF (60 ml) was added dropwise to a suspension of magnesium (0.213 mol) in THF (60 ml) at room temperature under N ₂ flow. The mixture was stirred for 30 minutes. Cool the mixture to 0 ° C.,
A solution of intermediate (10) (0.071 mol) in THF (60 ml) was added dropwise and the mixture was stirred for 15 minutes. Mix the mixture with water and NH ₄ C
It was poured into and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH /
NH ₄ OH 100/0/0 to 90/10 / 0.1). The pure fractions were collected and the solvent was evaporated, leaving 22.4 g (9
0% of (±) -α- [4- (2-benzothiazolylamino) phenyl] -3-fluorobenzenemethanol (Intermediate 11) was obtained.

c) n-butyllithium (0.1836 mol; 1.6M) in THF
To a solution of N- (1-methylethyl) -2-propanamine (0.1836 mol) in (60 ml) was added dropwise at -70 ° C under N ₂ flow. The mixture was stirred for 20 minutes, during which time the mixture was -30 ° C.
Was heated up. A solution of ethyl propanoate (0.1836 mol) in THF (100 ml) was added at -78 ° C. The mixture is −
Warmed to 30 ° C and then cooled to -78 ° C. THF (60m
A solution of intermediate (10) (0.0875 mol) in l) was added dropwise. The mixture was stirred at −60 ° C. for 20 minutes, then water and NH 3.
Poured into ₄ Cl and extracted with EtOAc. Separate the organic layer,
Dry, filter and evaporate the solvent. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ O
H / NH ₄ OH 97/3 / 0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered and dried, yielding 18 g of ethyl (±) -4- (2-benzothiazolylamine) -β-hydroxy-α-methylbenzenepropanoate (Intermediate 12).

Example A-5 a) 3-Bromopentane (0.3 mL in (C ₂ H ₅ ) ₂ O (200 ml).
A solution of 31 mol) was added dropwise to a solution of magnesium turnings (0.331 mol) in (C ₂ H ₅ ) ₂ O and the mixture was stirred at room temperature for 2 hours and then cooled to 0 ° C. THF
A solution of N- (4-formyl-phenyl) acetamide (0.11 mol) in (400 ml) was added dropwise and the mixture was stirred for 10 minutes. The mixture was poured into aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was dried, filtered and the solvent was evaporated.
Column residue on silica gel chromatography and purified by (eluent _{CH 2 Cl 2 / CH 3 OH} / NH 4 OH 97/3 / 0.1). The pure fractions were collected and the solvent was evaporated,
13.5 g (52%) of (±) -N- [4- (2-ethyl-1)
-Hydroxybutyl) phenyl] acetamide (intermediate
13) got.

b) Methanesulfonyl chloride (0.114 mol) was added to CH ₂ Cl ₂ (2
To a solution of intermediate (13) (0.057 mol) and triethylamine (0.114 mol) in 50 ml) was added dropwise at 0 ° C. under N ₂ and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated to give 17.86 g (100%) of (±) -4- (acetylamine) -α- (1-ethylpropyl) benzenemethanol methanesulphonate (Intermediate 14).

c) A mixture of intermediate (14) (0.187 mol), 1H-1,2,4-triazole (0.561 mol) and potassium carbonate (0.561 mol) in methanol (600 ml) was stirred and refluxed for 20 hours. The mixture was poured into water and extracted with CH ₂ Cl _2.
The organic layer was washed with water, dried, filtered and the solvent was evaporated. Column residue on silica gel chromatography and purified by (eluent _{CH 2 Cl 2 / CH 3 OH} / NH 4 OH 96/4 / 0.1). The pure fractions were collected, the solvent was evaporated and 22 g of (±) -N- [4- [2-ethyl-1- (1H
-1,2,4-Triazol-1-yl) butyl] phenyl] acetamide (41%) (intermediate 15) was obtained.

d) A mixture of intermediate (15) (0.0073 mol) in HCl (10 ml; 3N) was stirred at 60 ° C for 12 hours. The mixture was poured into ice water, basified with concentrated NaOH and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: C
H ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98.5 / 1.5 / 0.1). The pure fractions were collected and the solvent was evaporated.
The residue was crystallized from methyl ethyl ketone / DIPE. The precipitate was filtered, dried and 1.8 g (73%) of (±) -4-
[2-Ethyl-1- (1H-1,2,4-triazole-1-
Yield) butyl] -benzenamine (Intermediate 16) was obtained.
The products were separated by HLPC Chiralpack AS 20 μm (eluent: hexane / C ₂ H ₅ OH 65/35). The pure fractions were collected, the solvent was evaporated and dried to give 0.54g of (A) -4- [2-ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] benzene. Amine (Intermediate 1
7) and 0.588 g of (B) -4 [2-ethyl-1- (1H
-1,2,4-triazol-1-yl) butyl] benzenamine (Intermediate 18) was obtained.

e) A mixture of CS ₂ (0.0819 mol) in NaOH (3.8 ml; 20N) was added to the intermediate (16) in dimethylsulfoxide (37 ml).
To a mixture of (0.063 mol) was added at room temperature. The mixture was stirred for 1 hour and cooled to 0 ° C. Iodomethane (4.9m
l) was added. The mixture was stirred at room temperature for 3 hours and cooled to 0 ° C. NaOH (3.8 ml; 20N) and iodomethane (4.9 ml) were added. The mixture was stirred at room temperature overnight. E
tOAc and water were added and the mixture was extracted with EtOAc. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated to give 25 g of (±) -N- [bis (methylthio) methyl] -4- [2-ethyl-1- (1H -1,2,4-Triazol-1-yl) butyl] benzenamine (Intermediate 19
got a).

f) Carbonothioic acid dichloride (0.216 mol) was added dropwise at 0 ° C to a solution of intermediate (16) (0.1665 mol) in sodium hydroxide (3N; 72.15 ml) and CH ₂ Cl ₂ (400 ml). The mixture was allowed to warm to room temperature over 2 hours with stirring and then poured into K ₂ CO ₃ (10%; 200 ml). The mixture was stirred for 30 minutes and then decanted. The organic layer was dried, filtered and the solvent was evaporated to give 47.7 g (100%) of (±) -1- [2-ethyl-1- (4-isothiocyanatophenyl) butyl] -1H-1, 2,4-triazole (intermediate 19b) was obtained.

(±) -1- [1- (4-Isothiocyanatophenyl) -2-ethylbutyl] -1H-imidazole (intermediate
19c) was similarly prepared.

Example A-6 a) 1- (4- in 4-methoxyethanol (200 ml)
Aminophenyl) -2-methyl-1-propanone (0.06
A mixture of 37 mol) and methyl 2-chloro-3-pyridinecarboxylate (0.0637 mol) was stirred and refluxed for 90 hours. The mixture was dissolved in water and EtOAc and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated to give 22.6 g of methyl 2-[[4- (2-methyl-1-oxopropyl) phenyl] amino] -3-pyridinecarboxylate (intermediate). I got a body 20).

b) sodium tetrahydroborate (0.0764 mol),
Intermediate (20) (0.0637 mol) in methanol (200 ml)
Was added to the above mixture in small portions at 0 ° C. The mixture was stirred for 2 hours. Water was added and the organic layer was evaporated. The concentrate was dissolved in CH ₂ Cl ₂ , dried, filtered and the solvent was evaporated to give 18.38 g of (±) -2-[[4- (1-hydroxy-
Obtained methyl 2-methylpropyl) phenyl] amino] -3-pyridinecarboxylate (Intermediate 21).

Example A-7 a) Aluminum (III) chloride (0.666 mol) was added to 1,2-
A solution of N-phenyl-2-benzothiazolylamine (0.222 mol) and 1,2-dichloro-1-propanone (0.233 mol) in dichloroethane (500 ml) was added portionwise at room temperature and the mixture was stirred. The mixture was heated at 80 ° C for 2 hours.
The mixture was poured into ice and extracted with CH ₂ Cl _2. The organic layer was decanted, dried, filtered and the solvent was evaporated, 68 g
(±) -1- [4- (2-benzothiazolylamino)
Phenyl] -2-chloro-1-propanone (95.7%)
(Intermediate 22) was obtained.

b) A mixture of intermediate (22) (0.0423 mol), N-methylethanamine (0.084 mol) and potassium carbonate (0.127 mol) in methanol (150 ml) was stirred and refluxed for 90 minutes. The mixture was poured into water, extracted with CH ₂ Cl ₂ and decanted. The organic layer was dried, filtered and the solvent was evaporated. Column residue on silica gel chromatography and purified by (eluent CH ₂ Cl _2/2-propanol / NH ₄ OH 95/5 / 0.1 and 90/10 / 0.1). The pure fractions were collected, the solvent was evaporated and 6.85 g (54%) of (±) -1- [4- (2-benzothiazolylamino)-
Phenyl] -2- (ethylmethylamino) -1-propanone (intermediate 23) was obtained.

In a similar manner, (±) -1- [4- (2-benzothiazolylamine) phenyl] -2- (dimethylamino)-
1-Propanone (intermediate 24) was prepared.

c) Sodium borohydride (0.0642 mol) in a solution of intermediate 24 (0.0584) in methanol (250 ml) 0--
Aliquots were added at 5 ° C and the mixture was stirred for 3 hours. The mixture was poured into water and extracted with CH ₂ Cl _2. The organic layer was decanted, dried, filtered and the solvent was evaporated to give 45 g of (±) -4- (2-benzothiazolylamine) -α-
[1- (Dimethylamino) ethyl] benzeneethanol (intermediate 25) was obtained.

Example A.8 a) The following reactions were carried out under N ₂ atmosphere. THF (2700 ml)
A mixture of N- (4-bromophenyl) -2-benzothiazolamine (0.492 mol) in was stirred at -70 ° C.
Butyllithium (0.984 mol; 2.5M in hexane) -6
It was added dropwise at 5 ° C. The mixture was stirred for 1 hour. THF (300m
A solution of 2-ethyl-butanal (0.492 mol) in 1) was added dropwise at -75 ° C. The mixture was warmed to room temperature overnight.
Aqueous 10% NH ₄ Cl solution (3000 ml) was added and the mixture was stirred for 15 minutes. The separated aqueous layer was extracted with EtOAc (1000 ml). The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from methyl isobutyl ketone. The precipitate was filtered, dried and 109 g (68%) of (±) -4-
(2-Benzothiazolylamine) -α- (1-ethyl-
Propyl) benzenemethanol (intermediate 28) was obtained.

b) A mixture of intermediate 28 (0.156 mol) and triethylamine (0.312 mol) in CH ₂ Cl ₂ (500 ml) was stirred at 0 ° C. under a stream of N ₂ . A mixture of methylsulfonyl chloride (0.314 mol) in CH ₂ Cl ₂ (500 ml) was added dropwise. Mixture 0
The mixture was stirred at 0 ° C for 3 hours. The solvent was evaporated to give methanesulfonic acid (±) -4- (2-benzothiazolylamino) -α.
-(1-Ethylpropyl) -benzenemethanol (ester) (intermediate 26) was obtained.

c) Toluene (150 ml) was added to intermediate 28 (0.0582 mol). The heterogeneous mixture was stirred at room temperature. A solution of thionyl chloride (0.0644 mol) in toluene (50 ml) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0 ° C. The precipitate was filtered, dried at room temperature and 25 g of (±) -N- [4- (1-chloro-2-ethylbutyl)).
Phenyl] -2-benzothiazolamine monohydrochloride (Intermediate 29) was obtained.

Example A.9 (±) -α- (1-Ethylpropyl) -4-[[2- (methylthio), prepared according to the procedure described in Example A.2.e, in methanol (144 ml). A mixture of -4-pyrimidinylamino] benzene-methanol (0.0227 mol) was hydrogenated for 2 days at room temperature using Raney nickel (7.2 g) as catalyst. After uptake of hydrogen (1 eq), the catalyst was filtered through Celite, washed with methanol and the filtrate was evaporated. Column residue by chromatography on silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH 95/5) and purified by. The desired fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered, dried and 1.02 g (17%) of (±) -α-
(1-Ethylpropyl) -4- (4-pyrimidinylamino) benzenemethanol (Intermediate 27) was obtained.

Example A.10 a) Compound 130 (0.009 mol) was added to thionyl chloride (40 ml) at 0 ° C. The mixture was stirred at 0 ° C for 90 minutes. The solvent was evaporated to give 3.5 g of N- [4- [2- (dimethylamino) -1- (1-methyl-1H-imidazol-5-yl) -1-propenyl] phenyl] -2-benzothiazoleamine. (Intermediate 56) was obtained.

b) Using a reaction procedure similar to that described in Example B-12 below, N- [4- [2-ethyl-1- (1-methyl-
1H-Imidazol-2-yl) -1-butenyl] phenyl] -2-benzothiazolamine (Intermediate 57) was prepared.

The following intermediates are intermediates that do not contain chiral carbon atoms.
All but 55 were racemic mixtures and were prepared according to any one of the above procedures.

B) Preparation of final compound Example B-1 A mixture of intermediate (9) (0.0125 mol), 1H-imidazole (0.0584 mol) and potassium carbonate (0.0586 mol) in methanol (300 ml) was stirred and refluxed for 12 hours. did. The solvent was evaporated and the residue was taken up in water and CH ₂ Cl _2. The organic layer was separated, dried, filtered and the solvent was evaporated. Column residue on silica gel chromatography and purified by (eluent _{CH 2 Cl 2 / CH 3 OH} / NH 4 OH 96.5 / 3.5 / 0.2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE. The precipitate was filtered, dried and 1.65 g (28%) of N-
[4- (1H-Imidazol-1-ylmethyl) -phenyl] -2-benzothiazolamine (Compound 24) was obtained.

Example B-2 Triphenylphosphine (4.8 g) and 1H-1,2,4-
Triazole (0.018 mol) in THF (7)
To a solution of (0.00732 mol) was added at 5 ° C. under N ₂ flow. Then diethyl azodicarboxylate in THF (2.88m
The solution of l) was added, the mixture was allowed to come to room temperature and then stirred overnight. Add water, evaporate the solvent, HCl (3N)
Acidified with and separated layers. The aqueous layer was washed with EtOAc, NH ₄
Basified with OH and extracted with EtOAc. Separate the organic layer,
Dry, filter and evaporate the solvent. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ O
H / NH ₄ OH 96/4 / 0.5). The pure fractions were collected and the solvent was evaporated. The residue is converted to (C ₂ H ₅ ) ₂ O
Crystallized from. The precipitate is filtered, dried and dried to 1 g (49
%) Of (±) -N- [4- [2- (dimethylamino)-
2-Methyl-1- (1H-1,2,4-triazol-1-yl) propyl] phenyl] -2-benzothiazolamine (Compound 38) was obtained.

Example B-3 a) A mixture of intermediate (19b) (0.1665 mol) and 2-aminobenzenethiol (0.2 mol) in THF (500 ml) was stirred and refluxed overnight. The mixture was cooled, poured into water, extracted with CH ₂ Cl ₂ and decanted. The organic layer was dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH
₄ OH 97.5 / 2.5 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone / diethyl ether. The precipitate was filtered, dried and 31.2 g (49.6%) of (±) -N- [4-
[2-Ethyl-1- (1H-1,2,4-triazole-1-
Il) butyl] phenyl] -2-benzothiazolamine (Compound 25) was obtained.

b) Compound (25) (0.0265 mol) was separated and stationary phase Chir
Purified by chiral column chromatography on alcel OJ (eluent: hexane / ethanol 50/50). Two desired fraction groups were collected and their solvent was evaporated. Fraction 1 was crystallized from 2-propanol. The precipitate was filtered, washed with 2-propanol, then dried to give 2 g (20%) of (A) -N- [4
-[2-Ethyl-1- (1H-1,2,4-triazole-1
-Yl) butyl] phenyl] -2-benzothiazolamine (Compound 33) was obtained.

Fraction 2 was crystallized from 2-propanol.
The precipitate was filtered, dried and 1.9 g (19%) of (B) -N
-[4- [2-Ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzothiazolamine (Compound 34) was obtained. The corresponding filtrate of crystallized fraction 2 was evaporated. Part of the residue was dissolved in 2-propanol and the (E) -2-butenedioate (2:
Switched to 3). The precipitate was filtered, dried and 3 g of (B) -N- [4- [2-ethyl-1- (1H-1,2,4-
Triazol-1-yl) butyl] phenyl] -2-benzothiazolamine (E) -2-butene dihydrochloride (2:
3) (Compound 35) was obtained.

c) 2-methyl-2-propanol, potassium salt (0.01
27 mol) was added portionwise to a solution of compound (25) (0.0106 mol) in THF (30 ml) at 0 ° C and the mixture was cooled to 0 ° C.
And stirred for 10 minutes. Iodomethane (0.0 ml in THF (10 ml)
127 mol) was added slowly and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water and extracted with CH ₂ Cl _2. The organic layer was separated, dried, filtered and the solvent was evaporated. Column residue on silica gel chromatography and purified by (eluent _{CH 2 Cl 2 / CH 3 OH} / NH 4 OH 98.5 / 1.5 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered and dried. The residue was recrystallized from 2-butanone. The precipitate is filtered, dried and dried to 1.5 g (36
%) Of (±) -N- [4- [2-ethyl-1- (1H-1,
2,4-triazol-1-yl) butyl] phenyl]-
N-methyl-2-benzothiazolamine (Compound 32)
Got

Example B-4 a) NaOH (6.35 ml; 20N) was added to dimethyl sulfoxide (11
2-aminobenzenethiol (0.0637 mol) in 5 ml)
To the above solution at room temperature. The mixture was stirred at room temperature for 30 minutes. (±) -β- prepared according to intermediate (19a)
[4-[[bis (methylthio) methylene] amino] phenyl] -N, N, α-trimethyl-1H-imidazol-1-
Ethanamine (0.0637 mol) was added. 110 mixture
Stir overnight at ° C, then pour into ice, extract with EtOAc, and wash with HCl (3N). The aqueous layer was basified with concentrated NH ₄ OH, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97 /
3 / 0.1 and 90/10 / 0.1). Two pure fractions (F1 and F2) were collected and their solvent was evaporated. F1 was crystallized from 2-propanone. The precipitate was filtered and dried. The residue was dissolved in K ₂ CO ₃ (10%), filtered and the solvent was evaporated to give 1.12 g (5%) of (±)-(A) -N- [4- [2- (dimethylamino).
-1- (1H-imidazol-1-yl) propyl] phenyl] -2-benzothiazolamine (Compound 1) was obtained. F2 was crystallized from 2-propanone. The precipitate was filtered and dried. The residue was recrystallized from 2-propanone. The precipitate was filtered, dried and 0.9 g (4%) of (±)
-(B) -N- [4- [2- (dimethylamino) -1-
(1H-imidazol-1-yl) propyl] phenyl]
2-benzothiazolamine (Compound 2) was obtained.

b) Compound (2) (0.021 mol) was added to HPLC Chiralpack A
S (eluent: hexane _{/ C 2 H 5 OH 87 /} 13~70 / 30) was separated by. The pure fractions were collected and the solvent was evaporated. Fraction 1 was dissolved in DIPE. The precipitate was filtered, dried and 2.54 g of (B1) -N- [4- [2-
(Dimethylamino) -1- (1H-imidazol-1-yl) propyl] phenyl] -2-benzothiazolamine (32%) (Compound 3) was obtained. Fraction 2 was dissolved in diethyl ether. The precipitate was filtered, dried and 2.41 g of (B2) -N- [4- [2- (dimethylamino) -1- (1H-imidazol-1-yl) propyl].
Phenyl] -2-benzothiazolamine (30.3%)
(Compound 4) was obtained.

Example B-5 a) 1,1′-Carbonylbis-1H-imidazole (0.122
Mol) was added at 60 ° C. to a mixture of intermediate (21) (0.0612 mol) in THF (250 ml). The mixture was stirred overnight, poured into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ /
CH ₃ OH / NH ₄ OH 99.25 / 0.75 / 0.1). The pure fractions were collected and the solvent was evaporated. Some of the residue (2 g) was crystallized from CH ₃ OH / 2-propanone / DIPE. The precipitate is filtered, dried and 1.6 g (40%) (±)
-2-[[4- [1- (1H-imidazol-1-yl)
Methyl 2-methylpropyl] phenyl] amino] -3-pyridinecarboxylate (Compound 52) was obtained.

b) lithium aluminum hydride (0.0242 mol) in TH
To F (200 ml) was added in small portions at 0 ° C. under N ₂ flow.
A solution of compound (52) (0.022 mol) in THF (200 ml) was added dropwise at 0 ° C. The mixture was stirred for 7 hours then cooled to 0 ° C., hydrolyzed with EtOAc and water and filtered through Celite. The solvent was evaporated to give 6.5 g (93%) of (±) -2-[[4- [1- (1H-imidazol-1-
Il) -2-methylpropyl] phenyl] -amino]-
3-Pyridinemethanol (Compound 54) was obtained.

c) A mixture of compound (54) (0.02 mol) and manganese (IV) oxide (65 g) in CH ₂ Cl ₂ (200 ml) was added at room temperature to 16
Stir for hours. The mixture was filtered through Celite and the solvent was evaporated to give 5.2 g (81%) of (±) -2-[[4-
[1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] amino] -3-pyridinecarboxaldehyde (Compound 55) was obtained.

Example B-6 2-phenoxy-1,3-benzoxazole (0.0123
Mol) was added to a solution of intermediate (16) (0.0123 mol) in N, N-dimethylformamide (20 ml). The mixture was stirred and refluxed at room temperature for 12 hours and then overnight.
EtOAc was added. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. Column residue by chromatography on silica gel (eluent: cyclohexane / 2-propanol _{/ NH 4 OH 90/10 /} 0.5) and purified by. The pure fractions were collected and the solvent was evaporated. DI residue
Crystallized from PE. The precipitate is filtered, dried and 2.04g
(49.5%) of N- [4- [2-ethyl-1- (1H-1,2,
4-triazol-1-yl) butyl] phenyl] -2
-Benzoxazolamine (compound 56) was obtained.

Example B-7 A mixture of 1-chloro-2-propanone (1.08 ml) and intermediate (2) (0.0123 mol) in ethanol (20 ml) was stirred and refluxed for 3 hours. The mixture was cooled and the solvent was evaporated. The residue was dissolved in CH ₂ Cl ₂ and washed with K ₂ CO ₃ (10%) and water. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanone and _{(C 2 H 5) 2 O} , 3.08g of (80%) (±) -N- [4- [1- (1H
-Imidazol-1-yl) -2-methylpropyl] phenyl] -4-methyl-2-thiazolamine (compound
50) was obtained.

Example B-8 A mixture of intermediate (2) (0.0269 mol) and 2-bromo-1,1-diethoxyethane (0.035 mol) in HCl (11.8 ml; 3N) and ethanol (200 ml) was stirred and Refluxed for 3 hours. The mixture was cooled and evaporated. CH ₂ C residue
It was dissolved in ₁₂ and K ₂ CO ₃ (10%) and extracted with CH ₂ Cl ₂ . The organic layer was washed with water and _{K 2 CO 3 (10%)} , dried, filtered and the solvent evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH
₄ OH 96/4 / 0.2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE to give 0.9 g (11%) of (±) -N
-[4- [1- (1H-imidazol-1-yl) -2-
Methylpropyl] phenyl] -2-thiazolamine (Compound 51) was obtained.

Example B-9 Acetic acid methanimidamide (0.0309 mol) was added to intermediate 113 (0.0155) in 1-methyl-2-pyrrolidinone (35 ml).
Mol) solution. The mixture was stirred, refluxed for 2 hours, then cooled, poured into water and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue (28.4g) on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 96/4 / 0.1)
Purified by. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH ₃ OH. The precipitate is filtered, washed with diethyl ether, dried and 1.66g
Of ^{(±) -N 2 - [4-} [2- ethyl--1- (1H-1,2,4
-Triazol-1-yl) butyl] phenyl] thiazolo [5,4-d] pyrimidin-2,7-diamine (compound 11
7) got.

Intermediate 43 in Example _{B-10 CH 3 OH (81ml} ) (0.0089 mol) and CH ₃
Stir a mixture of 30% CH ₃ ONa (0.0445 mol) in OH,
Reflux for hours. The mixture is cooled, poured into water, NaCl
Saturated with and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (3.3 g) was subjected to column chromatography on silica gel (eluent: CH ₂ Cl ₂ /
CH ₃ OH / NH ₄ OH 95/5 / 0.2; 15-40 μm). Two pure fractions were collected and their solvent was evaporated. Fraction 1 was crystallized from 2-butanone and diethyl ether. The precipitate was filtered, dried and 0.6 g of (A) -N- [1- [1- (1H-imidazol-1-yl) -3-methoxy-2-methylpropyl] phenyl] -2-benzo Thiazolamine (Compound
86) was obtained.

EXAMPLE B-11 NaBH ₃ CN (0.009 mol), a solution of methanol (100ml) Intermediate 56 in (0.009 mol) was added in small portions under N ₂ stream under -4 ° C.. The mixture is stirred for 1 hour and K ₂ CO ₃ 10
% And ice and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂
Cl ₂ / CH ₃ OH / NH ₄ OH 95.5 / 4.5 / 0.2 to 93/7 / 0.3; 15 to 40μ
Purified by m). Two pure fractions were collected and their solvent was evaporated. The residue was crystallized from 2-butanone. The precipitate was filtered, washed with diethyl ether, dried and 0.61 g of (B) -N- [4- [2-
(Dimethylamino) -1- (1-methyl-1H-imidazol-5-yl) propyl] phenyl] -2-benzothiazolamine (18%) (Compound 109) was obtained.

Example B-12 SnCl ₂ (0.156 mol) and HCl 12N (0.562 mol)
Was added to a mixture of compound 126 (0.039 mol) in acetic acid (159 ml). The mixture was stirred and refluxed overnight, then poured into ice, basified with concentrated NH ₄ OH solution and extracted with CH ₂ Cl _2. The organic layer was separated, filtered through Celite,
Dry, filter and evaporate the solvent. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ O
H / NH ₄ OH 97.5 / 2.5 / 0.2; 15-40 μm). The pure fractions were collected and the solvent was evaporated.
The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered, dried and 1.19 g (8%) of (±) -N- [4- [2-ethyl-1- (1-methyl-
1H-imidazol-2-yl) butyl] phenyl] -2
-Benzothiazolamine (compound 110) was obtained.

Example B-13 Compound 34 (0.0053 mol) was added to boiling ethyl acetate (15 ml).
Dissolved in. H ₃ PO ₄ (85%; 2.5 ml) was added dropwise with stirring. An oily precipitate formed. The supernatant was removed by decantation and 2-propanone (20 ml) was poured into the residual oil. The mixture was vigorously stirred. The precipitate was filtered, dried and 3.0 g (82%) of (B) -N- [4-
[2-Ethyl-1- (1H-1,2,4-triazole-1-
Il) butyl] phenyl] -2-benzothiazolamine monohydrate phosphate (1: 3) (Compound 87) was obtained.

Example B-14 Intermediate (26) (0.156 mol), 1H in CH ₃ CN (800 ml)
-1,2,4-triazole (0.313 mol) and K ₂ CO ₃ (0.3
(13 mol) was stirred and refluxed for 12 hours. The solvent was evaporated. The residue was dissolved in _{CH 2 Cl 2 / H 2 O} . The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl
It was purified by _{2 / CH 3 OH / NH 4} OH 98/2 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered, dried and 16.8 g of (±) -N- [4- [2-ethyl-1- (1
H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzothiazolamine (26%) (Compound 2
5) got.

Example B-15 n-Butyllithium (1.6M; 0.0607 mol) was added with THF (60
1-methyl-1H-imidazole (0.0607 mol) in
Was added dropwise to the above solution at -70 ° C under N ₂ gas stream. -70 the mixture
Stirred at 30 ° C for 30 minutes. Intermediate 24 (0.024 in THF (60 ml)
3 mol) mixture was added dropwise. The mixture was stirred, poured into water and NH ₄ Cl. The organic layer was separated, dried, filtered and the solvent was evaporated. Column chromatography of the residue on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 9
8/2 / 0.2). Two pure fractions were collected and their solvent was evaporated. The residue was crystallized from diethyl ether and methyl ethyl ketone.
The precipitate was filtered, dried and 2.4 g (24%) of (A) -α
-[4- (2-benzothiazolylamino) phenyl]-
α- [1- (dimethylamino) ethyl] -1-methyl-
1H-Imidazole-2-methanol (Compound 127) and 0.66 g (6%) of (B) -α- [4- (2-benzothiazolylamino) phenyl] -α- [1- (dimethylamino) ethyl. ] -1-Methyl-1H-imidazole-2-
Methanol (compound 128) was obtained.

Example B-16 (A) -α- [4- (2-benzothiazolylamino)
Phenyl] -α- [1- (dimethylamino) ethyl]-
1-Methyl-1H-imidazole-5-methanol (Compound 130), except that chlorotriethylsilane (equimolar as 1-methyl-1H-imidazole) was added to the reaction mixture before adding intermediate 24. Prepared in a manner similar to that described for Example B-15.

Example B-17 Intermediate 19 in 1-methyl-2-pyrrolidinone (40 ml)
A mixture of b (0.0409 mol) was added to the amino-propanedinitrile (0.04 ml) in 1-methyl-2-pyrrolidinone (100 ml).
45 mol) solution was added dropwise. The mixture was stirred at room temperature for 15 hours, then poured into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. Column residue on silica gel chromatography and purified by (eluent _{CH 2 Cl 2 / CH 3 OH} / NH 4 OH 97/3 / 0.1). The pure fractions were collected and the solvent was evaporated.
The residue was crystallized from methyl ethyl ketone and diethyl ether. The precipitate was filtered, dried and 0.96 g of (±) -5-amino-2-[[4- [2-ethyl-1-
(1H-1,2,4-triazol-1-yl) butyl] phenyl] amino-4-thiazole-carbonitrile (Compound 113) was obtained.

Tables 1-6 list compounds of formula (I) prepared according to one of the above examples.

Table 7 lists both experimental (column item "exp") and theoretical (column item "theor") elemental analysis values for carbon, hydrogen and nitrogen of the compounds prepared in the experimental section above. .

C. Pharmacological Examples Example C.1: Inhibition of retinoic acid (RA) metabolism MCF-7 human breast cancer cells were grown as stock cultures according to protocols known in the art. One day before the experiment, RA was added to the stock culture to stimulate RA metabolism.
At the start of the experiment, the cell suspension was incubated in tissue culture medium containing ³ H-RA as a substrate. Various concentrations of test compound (dissolved in 1% DMSO) were added to the incubation mixture and unmetabolized RA was separated from its polar metabolites at the end of the incubation. Fractions containing polar ³ H labeled metabolites were collected and counted in a scintillation counter. For each experiment, control and blank incubations were performed in parallel. Those test compounds, namely compound numbers 1-4, 8, 10, 16-18, 24,
25, 27, 29 to 31, 33, 34, 35, 37, 40, 44 to 47, 49 to 5
1, 53, 56 and 58 all had IC ₅₀ values less than 1 × 10 ⁻⁸ M. Here, the IC ₅₀ value is defined as the concentration required to reduce the amount of metabolites to 50% of the control.

Example C.2: Vaginal keratinogenesis test in ovariectomized rats Ovariectomized rats were subcutaneously injected with sesame oil containing 100 μg estradiol undecylate in a volume of 0.1 ml per 100 g body weight and control animals with sesame oil. Was injected. The test animals were orally (per o
s) A dose of test compound was treated once daily and control animals were treated with drug vehicle (PEG200). Last process 1
After a day, the animals were sacrificed and their vagina was examined for histological evaluation in J. Pharmacol. Exp. Ther. 261 (2), 773-779 (1).
992). 50 of test rats
The dose at which% showed complete inhibition of the estradiol undecylate-induced keratinogenic effect is defined as the active dose. Compound No. 2-5, 8, 15-19, 25, 27-29, 31, 32, 34, 4
2, 46 and 56 all had a lowest active dose (LAD) equal to or less than 2.5 mg / kg. The other compounds tested had LAD greater than 2.5 mg / kg.

D. Composition Examples The following formulations exemplify typical pharmaceutical compositions suitable for systemic or topical administration to animal and human subjects according to the present invention.

The "active ingredient" used throughout these examples (A.
I.) relates to compounds of formula (I) or their pharmaceutically acceptable acid addition salts.

Example D.1: Oral solution 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3 liters of this solution, first add 10 g
Dissolve 2,3-dihydroxybutanedioic acid, then 20 g of A.
I. was dissolved. The latter solution was combined with the rest of the former solution, to which 12 liters of 1,2,3-propane-triol and 3 liters of sorbitol 70% solution were added.
40 g of saccharin sodium was dissolved in 0.5 liter of water and 2 ml of raspberry and 2 ml of extract of currant were added. The latter solution and the former solution were combined and an appropriate amount of water was added to a volume of 20 liters to obtain an oral solution containing 5 mg of AI per teaspoon (5 ml). The resulting solution was filled in a suitable container.

Example D.2: Oral Drops 500 g AI in 60 liters in 0.5 liter 2-hydroxypropanoic acid and 1.5 liter polyethylene glycol.
Melted at -80 ° C. After cooling to 30-40 ° C, 35 liters of polyethylene glycol were added and the mixture was stirred well. Then a solution of 1750 g of sodium saccharin in 2.5 liters of purified water is added and 2.5 with stirring.
10 mg cocoa flavor and 10 mg with the appropriate amount of polyethylene glycol added to a volume of 50 liters
An oral drop solution containing / ml AI was obtained. The resulting solution was filled in a suitable container.

Example D.3: Capsules 20 g AI, 6 g sodium lauryl sulphate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide and 1.2 g magnesium stearate were vigorously stirred together. Subsequently, the mixture obtained is filled into 1000 suitable hard gelatin capsules, each containing 20 mg.
Did not include AI.

Example D.4: Injectable solution 0.5 mg AI, 1.50 mg anhydrous glucose and 0.332 ml
Concentrated hydrochloric acid was mixed with 0.8 ml of water for injection. pH = 3.2
Sodium hydroxide was added to ± 0.1 and water was added to 1 ml. The solution was sterilized and filled into sterile containers.

Example D.5: Preparation of film coated tablet tablet cores After thoroughly mixing a mixture of 100 g AI, 570 g lactose and 200 g starch, 5 g sodium dodecyl sulphate and 10 g polyvinylpyrrolidone (K
Moistened with a solution of ollidon-K90 ™). The moist powder mixture was screened, dried and screened again. Then 100 g microcrystalline cellulose (Avicel ™) and 15 g hydrogenated vegetable oil (Sterotex ™) were added. The whole is mixed well and compressed into tablets to get 10,000 tablets,
Each comprised 10 mg of active ingredient.

Coating 10 g methylcellulose (M in 75 ml denatured ethanol
To a solution of ethocel60HG ™), 5 g of ethyl cellulose (Ethocel22cps ™) in 150 ml of dichloromethane
Solution was added. Then 75 ml dichloromethane and 2.5 ml 1,2,3-propanetriol were added. 10 g
Of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. Add the latter solution to the former solution,
Then 2.5 g magnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml thick colored suspension (Opaspray
K-1-2109 ™) was added and the whole was homogenized. Tablet cores were coated in a coater with the mixture thus obtained.

Example D.6: 2% cream 75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearate and 10 mg isopropyl myristate were introduced into a double wall jacketed container until the mixture was completely melted. To heat. This mixture was added to purified water, 200 mg of pyropyrene glycol and 15 m
To a separately prepared mixture of g of polysorbate 60 having a temperature of 70-75 ° C. is added using a homogenizer for liquids. The resulting emulsion is mixed at 25 ° C with continuous mixing.
Allow to cool below. Then 20 mg AI, 1 mg polysorba
A solution of te80 and purified water and a solution of 2 mg anhydrous sodium sulfite in purified water is added to the emulsion with continued mixing. Homogenize the cream, 1 g AI, and fill into a suitable tube.

Example D.7: 2% Topical Gel To a solution of 200 mg hydroxypropyl b-cyclodextrin in purified water is added 20 mg AI with stirring. Hydrochloric acid is added until complete dissolution, then sodium hydroxide is added to pH 6.0. 50 mg of this solution
Add to a dispersion of 10 mg carrageenan PJ in propylene glycol with mixing with mixing. With slow mixing, heat the mixture to 50 ° C, allow to cool to about 35 ° C, then 50
Add 95% ethyl alcohol 95% (v / v). Add the required amount of the required amount of purified water to 1 g and mix the mixture until homogeneous.

Example D.8: 2% Topical Cream To a solution of 200 mg hydroxypropyl b-cyclodextrin in purified water is added 20 mg AI with stirring. Add hydrochloric acid until completely dissolved, then pH 6.0
Add sodium hydroxide until. With stirring, 50 mg glycerol and 35 mg polysorbate 60 are added and the mixture is heated to 70 ° C. The resulting mixture is 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg
Of cetyl alcohol, 20 mg of glycerol monostearate and 15 mg of sorbate 60 having a temperature of 70 ° C. are added with gradual mixing. After cooling below 25 ° C., 1 g of the required amount of the remainder of purified water is added and the mixture is mixed until homogeneous.

Example D.9: 2% Liposome Formulation 2 g AI (micro), 20 g phosphatidylcholine, 5
A mixture of g cholesterol and 10 g ethyl alcohol is stirred, heated at 55-60 ° C until completely dissolved, and 0.2 g methylparaben, 0.02 g propylparaben, 0.15 g disodium edetate (in purified water). disodiu
medetate) and 0.3 g of sodium chloride solution with homogenization. The appropriate amount of purified water required for 100 g is 0.
Add 15 g of hydroxypropyl methylcellulose,
Continue mixing until swelling is complete.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4439 A61K 31/4439 31/454 31/454 31/4725 31/4725 31/496 31/496 31/497 31/497 31/498 31/498 31/501 31/501 31/502 31/502 31/506 31/506 31/517 31/517 31/519 31/519 31/52 31/52 31/5377 31/5377 A61P 35 / 00 A61P 35/00 43/00 105 43/00 105 C07D 401/12 C07D 401/12 403/12 403/12 413/12 413/12 473/34 361 473/34 361 513/04 343 513/04 343 351 351 (72) Inventor Laclamp, Jijan Huernin Armand France Ef-76240 Lemesnil-Esnard Siyumandeu Pond Larsille 15 (72) Inventor Saint-Jejarard Syarur France Ef-76240 Lemesnil-Esnard・ Ryuarufurude Yune 6 (5 6) References International Publication 96/015118 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 417/12 A61K 31/4184 A61K 31/423 A61K 31/427 A61K 31/437 A61K 31/4439 A61K 31/454 A61K 31/4725 A61K 31/496 A61K 31/497 A61K 31/498 A61K 31/501 A61K 31/502 A61K 31/506 A61K 31/517 A61K 31/519 A61K 31/52 A61K 31 / 5377 A61P 35/00 A61P 43/00 105 C07D 401/12 C07D 403/12 C07D 413/12 C07D 473/34 361 C07D 513/04 343 C07D 513/04 351 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] 1. A formula In the formula, R ¹ represents hydrogen, hydroxy, C ₁ -C ₆ alkyl or aryl; R ² is hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; C _2-
C ₈ alkenyl; aryl; pyrrolidinyl optionally substituted with C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyloxycarbonyl; or C ₃ -C ₇ cycloalkyl,
Hydroxy, C ₁ -C ₄ alkyloxy, cyano, amino,
Mono- and di (C ₁ -C ₄ alkyl) amino, mono- and di (aryl) -amino, aryl C ₁ -C ₄ alkylamino, (C ₁ -C ₄ alkyl) (aryl C ₁ -C ₄ alkyl)
Amino, pyrrolidinyl, piperidinyl, optionally C _1-
Piperazinyl optionally substituted with C ₄ alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C ₁
-C ₄ alkyloxycarbonyl, aminocarbonyl, mono- and di (C ₁ -C ₄ alkyl) aminocarbonyl, C ₁ -substituted by one or two substituents selected from aryl, aryloxy and arylthio. represents C ₁₂ alkyl; R ³ is hydrogen, C ₁ -C ₆ alkyl, aryl; or represents a C ₁ -C ₆ alkyl substituted with aryl; Het is imidazolyl, triazolyl, unsaturated selected from tetrazolyl and pyridinyl Represents a heterocycle; each of the unsaturated heterocycles is optionally amino, mercapto, C _1-
Optionally substituted with C ₆ alkyl, C ₁ -C ₆ alkylthio or aryl; Represents an unsaturated monocyclic or bicyclic heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, purinyl, phthalazinyl, cinnolinyl, quinazolinyl and quinoxalinyl; Each of the bicyclic heterocycles is optionally hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo.
C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkylthio, formyl, carboxyl, mono- - or di (C ₁
-C ₆ alkyl) amino, one selected from C ₁ -C ₆ alkyloxycarbonyl or aryl, or two or three may be substituted with a substituent; or Is an expression Wherein each X is independently NR ⁸ , O, S, S (= O) or S (=
O) ₂ ; R ⁸ is hydrogen, C ₁ -C ₆ alkyl, aryl or aryl C ₁ -C ₆ alkyl; R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halo, cyano, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁
-C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- - or di (C ₁ -
C ₆ alkyl) represents amino, C ₁ -C ₆ alkyloxycarbonyl or aryl; -R ⁶ -R ⁷ - is the ^{formula: -CR 9 = CR 9 -CR 9} = CR 9 -, (b-1); - ^{N = CR 9 -CR 9 = CR} 9 -, (b-2); -CR 9 = N-CR 9 = CR 9 -, (b-3); -CR 9 = CR 9 -N = CR 9 -, ^{(b-4); -CR 9} = CR 9 -CR 9 = N-, (b-5); -CR 9 = N-N = CR 9 -, (b-6); -CR 9 = N-CR ^{9 = N-, (b-7} ); -CR 9 = CR 9 -N = N-, (b-8); -N = N-CR 9 = CR 9 -, (b-9); -N = ^{CR 9 -N = CR 9 -,} (b-10); -N = CR 9 -CR 9 = N-, (b-11); -CR 9 = N-N = N-, (b-12); ^{= N-, -N = CR 9 -N} (b-13); -N = N-CR 9 = N-, (b-14); -N = N-N = CR 9 -, (b-15) Represents a divalent group of, where each R ⁹ is Hydrogen, hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- Or represents di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkyloxycarbonyl or aryl; aryl is phenyl; or hydroxy, halo, cyano, amino, mono- or di (C ₁ -C ₆ alkyl) ) Amino, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, hydroxy
Represents phenyl substituted with 1, 2 or 3 substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, formyl, carboxyl and C ₁ -C ₆ alkylcarbonyl; Alternatively, two adjacent carbon atoms on said phenyl may be substituted by one divalent group having the formula C ₁ -C ₁₂ alkanediyl or halo C ₁ -C ₁₂ alkanediyl , Its N-oxides, pharmaceutically acceptable addition salts or stereochemically isomeric forms. 2. R ¹ represents hydrogen, C ₁ -C ₆ alkyl or aryl; R ² represents hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; C _2-
C ₈ alkenyl; aryl; or C ₃ -C ₇ cycloalkyl, hydroxy, C ₁ -C ₄ alkyloxy, cyano, amino, mono- and di (C ₁ -C ₄ alkyl) amino, mono-
And di (aryl) amino, aryl C ₁ -C ₄ alkylamino, (C ₁ -C ₄ alkyl) (aryl C ₁ -C ₄ alkyl) amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, perhydro-azepinyl, carboxyl, C ₁ -C ₄ alkyloxycarbonyl, aminocarbonyl, mono- - and di (C ₁ -C ₄ alkyl) aminocarbonyl, aryl, C ₁ substituted with one or two substituents selected from aryloxy and arylthio
Represents -C ₁₂ alkyl; Is 2-pyridinyl, 3-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 1-phthalazinyl, 3-cinnolinyl, 2-quinazolinyl, 4
-Represents an unsaturated monocyclic or bicyclic heterocycle selected from the group consisting of quinazolinyl and 2-quinoxalinyl;
Each of said unsaturated mono- or bicyclic heterocycles is optionally hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl,
One selected from C ₁ -C ₆ alkyloxy, formyl, carboxyl, mono- or di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkyloxycarbonyl or aryl,
It may be substituted with 2 or 3 substituents, or Is R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halo,
Nitro, amino, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy,
A formyl group, a carboxyl group, a mono- or di (C ₁ -C ₆ alkyl) amino group, a C ₁ -C ₆ alkyloxycarbonyl group or an aryl group, which is represented by the formula (a) or (b). The compound according to the item. 3. R ¹ represents hydrogen, hydroxy, C ₁ -C ₆ alkyl; R ² is hydrogen; C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; optionally C ₁ -C ₄ alkyl or Pyrrolidinyl optionally substituted with C ₁ -C ₄ alkyloxycarbonyl; aryl; or hydroxy, C ₁ -C ₄ alkyloxy, mono- and di (C ₁ -C ₄ alkyl) amino, (C ₁ -C _{4 1} ) selected from alkyl) (aryl C ₁ -C ₄ alkyl) amino, C ₁ -C ₄ alkyloxycarbonyl, morpholinyl, piperidinyl, piperazinyl optionally substituted with C ₁ -C ₄ alkyl, and aryloxy. Represents C ₁ -C ₁₂ alkyl substituted with one or two substituents; R ³ represents hydrogen and C ₁ -C ₆ alkyl; Het optionally substituted with C ₁ -C ₆ alkyl Good imidazolyl; It represents lysinyl or triazolyl; Is optionally substituted with hydroxy C ₁ -C ₆ alkyl, formyl or C ₁ -C ₆ alkyloxycarbonyl; 2-pyridinyl; 2-quinoxalinyl; 1-isoquinolinyl; 2-quinolinyl; optionally C ₁ -C 3-pyridazinyl optionally substituted with ₆ alkyl; purinyl; 2-pyrazinyl; 1-phthalazinyl; 4-quinazolinyl optionally substituted with aryl; 2-pyrimidinyl; optionally C ₁ -C ₆ alkylthio 4 which may be substituted
-Represents pyrimidinyl; or Represents a group of formula (a) or (b), wherein X represents NH, O or S; R ⁴ and R ⁵ are each independently hydrogen, hydroxy, nitro,
Cyano, amino, C ₁ -C ₆ alkyl or aryl, and —R ⁶ —R ⁷ — is represented by formula (b-1), (b-2) or (b-
10) divalent radicals in which each R ⁹ is independently hydrogen, C ₁
-C ₆ alkyl, hydroxy, halo, amino, halo C ₁ -C ₆
A compound according to claim 1 or 2 which represents alkyl or C ₁ -C ₆ alkyloxy. 4. Het is 1-imidazolyl optionally substituted with C ₁ -C ₆ alkyl or aryl; 2-imidazolyl optionally substituted with C ₁ -C ₆ alkyl; optionally C ₁ -C ₆ alkyl optionally substituted 5-imidazolyl; 1,3,4-triazol-1-yl and 1,2,4-triazol-1-claims-yl first term to third A compound according to any one of paragraphs. 5. There represents a group of formula (b), wherein, X represents O or S; and -R ⁶ -R ⁷ - represents a bivalent radical of formula (b-I), the range first of claims ~ The compound according to any one of items 4. 6. R ² is C ₁ -C ₁₂ alkyl; C ₃ -C ₇ cycloalkyl; aryl; or mono- or di (C ₁ -C ₄ alkyl) amino, C ₁ -C ₄ alkyloxycarbonyl or aryl. A compound according to any one of claims 1 to 5, which represents C ₁ -C ₁₂ alkyl substituted with oxy. 7. The compound is N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -2-benzothiazolamine; N- [4- [2-ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzoxa N- [4- [2-Ethyl-1- (1H-1,2,4-triazol-1-yl) butyl] phenyl] -2-benzothiazolamine; N- [4- [2- ( Dimethylamino) -1- (1H-imidazol-1-yl) propyl] phenyl] -2-benzothiazolamine; N- [4- [2- (dimethylamino) -1- (1H-1,2,
4-triazol-1-yl) propyl] phenyl]-
2-benzothiazolamine; N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -2-benzoxazolamine; N- [4- [2-ethyl-1- (1H-imidazole-1
-Yl) butyl] phenyl] -6-methoxy-2-benzothiazolamine; N- [4- [2- (dimethylamino) -1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] 2-benzothiazolamine; N- [4- [2- (dimethylamino) -2-methyl-1
-(1H-1,2,4-triazol-1-yl) propyl]
Phenyl] -2-benzothiazolamine; N- [4- [cyclohexyl (1H-imidazol-1-
Y-) methyl] phenyl] -2-benzothiazolamine; N- [4- [cyclohexyl (1H-1,2,4-triazol-1-yl) methyl] phenyl] -2-benzothiazolamine. Compounds according to item 1, their N-
Oxides, stereochemically isomeric forms or pharmaceutically acceptable addition salts. 8. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1-7. 9. A method according to claim 8 wherein the pharmaceutically acceptable carrier is intimately admixed with a therapeutically effective amount of a compound according to any one of claims 1 to 7. A method for producing the described composition. 10. A compound according to any one of claims 1 to 7 for use as a drug. 11. A formula (II) Where R ^{1 to} R ³ and Has the same meaning as in claim ¹ and W ¹ is a suitable leaving group, and an intermediate represented by: Het-H (III) or a functional derivative thereof [where Het is In a range inert to the reaction and in the presence of a suitable base, and optionally triphenylphosphine and diethyl azodicarboxylate or a functional derivative of any of the reagents. Reacting in the presence and, if desired, the compounds of formula (I) are converted into each other according to conversion methods known in the art, and further, if desired, the compounds of formula (I) can be treated with an acid. It is converted to a therapeutically active non-toxic acid addition salt by treatment, or to a therapeutically active non-toxic base addition salt by treatment with a base, or vice versa. Conversion to the free base, or the base addition salt is converted to the free acid by treatment with an acid; and, if desired, their stereochemically isomeric forms or N-
The method for producing the compound according to claim 1, wherein an oxide type is produced. 12. The formula (IV) In the formula, R ^{1 to} R ³ and Het have the same meanings as in claim 1, and an intermediate represented by the formula (V) In the formula, Is as defined in claim 1 and W ² is a suitable leaving group, wherein the intermediate is N-alkylated in a reaction-inert solvent and, optionally, of formula ( The compounds of formula I) are converted into each other according to conversion methods known in the art and, optionally, further the compounds of formula (I) are
Conversion to a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversion to a therapeutically active non-toxic base addition salt by treatment with a base, or vice versa.
The acid addition salt form is converted to the free base by treatment with alkali, or the base addition salt is converted to the free acid by treatment with acid; and also, if desired, their stereochemically isomeric or N-oxide forms are prepared. The method for producing the compound according to claim 1, wherein 13. Formula (VIII) In the formula, R ¹ , R ² and Het have the same meanings as in claim 1, and an intermediate represented by the formula (IX-1) Wherein —R ⁶ —R ⁷ — is as defined in claim 1, and is reacted with an intermediate represented by: in a reaction inert solvent; thus, a compound of formula (Ib-1) And a compound of formula (Ib-1) is optionally converted into each other according to conversion methods known in the art and, if desired, further of formula (I-b) a compound of b-1) is converted to a therapeutically active non-toxic acid addition salt by treatment with an acid, or a therapeutically active non-toxic base addition salt by treatment with a base, or Conversely, the acid addition salt form is converted to the free base by treatment with alkali, or the base addition salt is converted to the free acid by treatment with acid; and also, if desired, their stereochemically isomeric form or N-oxide. A method for producing a compound according to claim 1, wherein a mold is produced.